RRC ID 65299
Author Choi J, Sung JY, Lee S, Yoo J, Rongo C, Kim YN, Shim J.
Title Rab8 and Rabin8-Mediated Tumor Formation by Hyperactivated EGFR Signaling via FGFR Signaling.
Journal Int J Mol Sci
Abstract The epidermal growth factor receptor (EGFR) signaling is important for normal development, such as vulval development in Caenorhabditis elegans, and hyperactivation of the EGFR is often associated with cancer development. Our previous report demonstrated the multivulva (Muv) phenotype, a tumor model in C. elegans (jgIs25 strain) by engineering LET-23/EGFR with a TKI-resistant human EGFR T790-L858 mutant. Because Rab proteins regulate vesicle transport, which is important for receptor signaling, we screened the RNAi in the jgIs25 strain to find the Rabs critical for Muv formation. Herein, we show that rab-8 RNAi and the rab-8 (-/-) mutation effectively reduce Muv formation. We demonstrate that RABN-8, an ortholog of Rabin8, known as a GEF for Rab8, is also required for Muv formation by promoting the secretion of EGL-17/FGF from vulval precursor cells. In addition, FGFR inhibitors decreased Muv formation mediated by mutant EGFR. Our data suggest that Rab8 and Rabin8 mediate Muv formation through FGF secretion in the EGFR-TKI-resistant nematode model. Furthermore, FGFR-TKIs more effectively inhibit the growth of lung cancer cell lines in H1975 (EGFR T790M-L858R; EGFR-TKI-resistant) than H522 (wild-type EGFR) and H1650 (EGFR exon 19 deletion; EGFR-TKI-sensitive) cells, suggesting that FGFR-TKIs could be used to control cancers with EGFR-TKI-resistant mutations.
Volume 21(20)
Published 2020-10-20
DOI 10.3390/ijms21207770
PII ijms21207770
PMID 33092268
PMC PMC7589727
MeSH Animals Caenorhabditis elegans / genetics Caenorhabditis elegans / metabolism Carcinoma, Non-Small-Cell Lung / genetics Carcinoma, Non-Small-Cell Lung / metabolism* Carcinoma, Non-Small-Cell Lung / pathology Cell Line, Tumor Disease Models, Animal ErbB Receptors / genetics ErbB Receptors / metabolism* Erlotinib Hydrochloride / pharmacology Gefitinib / pharmacology Germinal Center Kinases / genetics Germinal Center Kinases / metabolism* Humans Lung Neoplasms / genetics Lung Neoplasms / metabolism* Lung Neoplasms / pathology Mutation Protein Kinase Inhibitors / pharmacology* Signal Transduction / drug effects Signal Transduction / genetics rab GTP-Binding Proteins / genetics rab GTP-Binding Proteins / metabolism*
Resource
C.elegans tm2526 tm2518